Functional brain imaging of childhood clinical disorders with PET and SPECT

During the first years of life, the human brain undergoes repetitive modifications in its anatomical, functional and synaptic construction to reach the complex functional organization of the adult central nervous system. Over the last decade, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have provided further insight into these maturation processes. This article reviews clinical and research applications of PET and SPECT in childhood disorders, with an emphasis on the specific contribution of these techniques in improving our knowledge about the pathophysiology of the developing brain.     

Neuroreceptor imaging of stress and mood disorders

Techniques such as positron emission tomography and single photon emission computed tomography allow for the imaging of neurotransmitter receptors and transporters in the brain. These tools have been used to investigate serotonergic, dopaminergic, and opioidergic function in healthy subjects as well as in patients with major depressive disorder, bipolar disorder, and other mood disorders. Pharmacologic challenges, such as amphetamine challenge, and physiologic stressors, such as pain challenge, have been used to further examine the function of these neurotransmitter systems. Neuroimaging of patient populations before and after medication treatment may be useful to understand changes in neurotransmission that accompany disease remission. As new radiotracers with higher selectivity for the various receptors and transporters are developed, imaging techniques may provide new insights into the pathophysiology of mood disorders, leading to improved diagnosis and treatment.     

Beyond monoamines: glutamatergic function in mood disorders

The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.     

Functional Neuroimaging in the Examination of Effects of Prenatal Alcohol Exposure

Functional neuroimaging offers the opportunity to understand the effect of prenatal alcohol exposure on the activities of the brain as well as providing a window into the relationship between neural activation and the behavioral outcomes that have been described in affected individuals. Several different methodologies have been used to examine the neurophysiological signal changes associated with different brain functions in prenatally exposed individuals and those diagnosed with fetal alcohol syndrome (FAS) or other fetal alcohol spectrum disorders (FASD). These include electroencephalography (EEG), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI). These studies demonstrate that it is feasible to use these technologies with this clinical population and that the damage to the central nervous system associated with prenatal alcohol exposure has widespread functional implications; however, currently, the literature in these areas is limited and unsystematic. Functional MRI with this clinical population has just begun to explore the implications of prenatal alcohol exposure with the first paper published in 2005. Other methodologies are similarly limited in scope. Nonetheless, these functional neuroimaging studies suggest that prenatal alcohol exposure, or a diagnosis of FAS, may lead to restrictions in neural efficiency or a global decrement in processing resources.     

认知心理生理学与无创性脑功能成像技术

无创性脑功能成像技术是认知心理生理学研究的重要手段。脑电图、事件相关电位、脑磁图、正电子发射断层摄影术、单光子发射计算机断层摄影术、功能磁共振成像和功能红外线成像等技术通过对人脑的电磁、新陈代谢、血流量、氧消耗、神经元活动等的测量来研究如视觉、注意、记忆、语言等认知活动及其与相关脑机制的相互关系。它们各有优缺点。     

Efficacy of noradrenergic-selective agents in the treatment of neuropsychiatric diseases

In recent years, a number of antidepressants with varying degrees of selectivity for the noradrenergic neurotransmitter system have become available. However, these agents represent a pharmacologically heterogeneous group and differ in terms of their precise side-effect profile and, possibly, their clinical efficacy. Bupropion, which is thought to act on both the dopamine and norepinephrine (NE) systems, has not been widely used as an antidepressant and has more recently been licensed as adjunctive therapy for smoking cessation. The serotonin-NE reuptake inhibitors venlafaxine and nefazodone, the noradrenergic and specific serotonergic antidepressant mirtazapine, and the selective NE reuptake inhibitor reboxetine (the only truly NE-selective agent available) have all demonstrated efficacy in the treatment of depressive disorders. Evidence is now emerging for their use in the treatment of anxiety and panic disorders. There is some suggestion of a role for noradrenergic agents in other disorders, including attention-deficit/hyperactivity disorder and social phobia. The full range of disorders for which noradrenergic agents can be used remains to be seen and further research in this area is necessary.     

Zur Aussagekraft von Neuroimaging-Befunden im Strafprozess

Over the last 30 years the forensic use of brain scanning technology in court has increased considerably. In the U.S. about two thirds of opinions involving positron emission tomography/single photon emission computed tomography (PET/SPECT) evidence are ruled admissible in court and often have a decisive impact on judges and juries. Undoubtedly, the impressive progress in modern functional imaging techniques has improved the differentiated knowledge on the neural basis of discrete aspects of crime-related cognition and behavior. However, there are several general issues which make it difficult to draw individual deductions concerning behavioral patterns from functional imaging results. By analyzing cases from the courtroom, the question will be addressed as to how far neuroimaging-based expert opinions are really supported by concrete findings in neurobiological research.     

Positron emission tomography methods with potential for increased understanding of mental retardation and developmental disabilities

Positron emission tomography (PET) is a technique that enables imaging of the distribution of radiolabeled tracers designed to track biochemical and molecular processes in the body after intravenous injection or inhalation. New strategies for the use of radiolabeled tracers hold potential for imaging gene expression in the brain during development and following interventions. In addition, PET may be key in identifying the physiological consequences of gene mutations associated with mental retardation. The development of high spatial resolution microPET scanners for imaging of rodents provides a means for longitudinal study of transgenic mouse models of genetic disorders associated with mental retardation. In this review, we describe PET methodology, illustrate how PET can be used to delineate biochemical changes during brain development, and provide examples of how PET has been applied to study brain glucose metabolism in Rett syndrome, serotonin synthesis in autism, and GABAA receptors in Angelman's syndrome and Prader-Willi syndrome. Future application of PET scanning in the study of mental retardation might include measurements of brain protein synthesis in fragile X syndrome and tuberous sclerosis complex, two common conditions associated with mental retardation in which cellular mechanisms involve dysregulation of protein synthesis. Mental retardation results in life-long disability, and application of new PET technologies holds promise for a better understanding of the biological underpinnings of mental retardation, with the potential to uncover new treatment options.     

Cognitive neuroscience from a behavioral perspective: A critique of chasing ghosts with geiger counters

Cognitive neuroscience is a growing new discipline concerned with relating complex behavior to neuroanatomy. Relatively new advances in the imaging of brain function, such as positron emission tomography (PET), have generated hundreds of studies that have demonstrated a number of interesting but also potentially problematic brain-behavior relations. For example, cognitive neuroscientists largely favor interpretations of their data that rely on unobserved hypothetical mechanisms. Their reports often contain phraseology such as central executive, willed action, and mental imagery. As B. F. Skinner argued for decades, cognitive constructs of neurological data may yield nothing more than a conceptual nervous system.     

Quantitative Anatomy: Power Beyond the Images

Positron emission tomography (PET) is a frontiermedical technology that, in contrast to the othercomputer-assisted technologies providing anatomicalpictures, produces functional images. I argue that PETalso opens up an avenue for shifting from images (asa tool for representation of biomedical data) back toanalysis of measurements (as a tool for quantificationof physiology). Admittedly, quantification of functionrequires structural constraints. I coined the emerginginterpretational framework quantitative anatomyin an attempt to conceptualize the PET merger betweenmeasuring and imaging, the two competing meansmedicine uses to examine the human body. Anatomyjustifies interpretations that fit the existingknowledge of a larger clinical audience, whilestatistical data possess an unexplored potential tointroduce mathematical rigor in the evaluation offunction, but are still a black box for the majorityof clinicians. This epistemological change is beingcarried out by PET users in action as well as indiscourse.     

Mirror neurons in humans: consisting or confounding evidence?

The widely known discovery of mirror neurons in macaques shows that premotor and parietal cortical areas are not only involved in executing one's own movement, but are also active when observing the action of others. The goal of this essay is to critically evaluate the substance of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies whose aim has been to reveal the presence of a parallel system in humans. An inspection of this literature suggests that there is relatively weak evidence for the existence of a circuit with 'mirror' properties in humans, such as that described in monkeys.     

Implications of the cAMP signaling pathway in psychiatric disorders: a systematic review of the evidence

The last decade has seen a shift in the theoretical framework addressing the pathophysiology of psychiatric disorders. During this period, research endeavors have been directed toward investigating the biochemical mechanisms involved in the transduction of information from the cell surface to the cell interior. The emerging picture, supported by growing evidence, is that in addition to neurotransmitters and their receptors, various signal transduction pathways may be linked to the pathophysiology of major psychiatric disorders. In this review, the role of one such pathway--the cyclic adenosine monophosphate (cAMP) signaling pathway--will be highlighted. We review data suggesting the involvement of the upstream and downstream components of this system in the pathophysiology of psychiatric disorders.     

The role of the glutamatergic system in posttraumatic stress disorder

Antiglutamatergic agents, such as lamotrigine, have been used successfully for the treatment of posttraumatic stress disorder (PTSD). They could be potentially acting through the stabilization of the corticotropin-releasing factor (CRF) systems. Glutamate mediates CRF release in various brain regions involved in the pathophysiology of PTSD, antiglutamatergic agents could stabilize the CRF system and, thereby, improve the symptom complex of PTSD (reexperiencing, hyperarousal, and avoidance). The role of glutamate and CRF in PTSD and other anxiety disorders are still being elucidated. However, it is clear that the glutamatergic systems play a role in the pathophysiology of PTSD.     

Noradrenergic pathology in psychiatric disorders: postmortem studies

In this paper, we review research utilizing postmortem brain tissue in order to investigate the potential neuropathology of the noradrenergic system in psychiatric disorders. The postmortem tissue approach to the study of the noradrenergic system has been used primarily in investigations of the biology of suicide and depression. Findings from postmortem studies provide data generally consistent with the hypothesis that a norepinephrine deficiency exists in depression, and possibly in the victims of suicide. However, postmortem studies do not presently provide irrefutable evidence of noradrenergic neuropathology. Technical shortcomings, issues of reproducibility, and the strengths of postmortem research are reviewed. More rigorously performed postmortem research is needed to aid researchers in pinpointing specific neuropathologies associated with psychiatric disease.     

Cerebellar norepinephrine modulates learning of delay classical eyeblink conditioning: evidence for post-synaptic signaling via PKA

The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks. To date, no studies have shown a direct involvement of cerebellar noradrenergic activity nor localized the post-synaptic response to cerebellar beta-noradrenergic receptor signaling. Using ipsilateral, localized infusions into cerebellar lobule HVI and interpositus (IP), we have established that blocking beta-noradrenergic receptors with propranolol significantly impairs acquisition of conditioned responses. Furthermore, interrupting activation of cAMP-dependent PKA in the cerebellum using Rp-cAMPS completely prevents acquisition. However, neither blocking beta-adrenergic receptors nor blocking PKA activation significantly interferes with performance of established conditioned responses when administered after the learned response is formed.     

Cholinergic modulation of learning and memory in the human brain as detected with functional neuroimaging

The advent of neuroimaging methods such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has provided investigators with a tool to study neuronal processes involved in cognitive functions in humans. Recent years have seen an increasing amount of studies which mapped higher cognitive functions to specific brain regions. These studies have had a great impact on our understanding of neuroanatomical correlates of learning and memory in the living human brain. Recently, advances were made to go beyond the use of fMRI as a pure cognitive brain mapping device. One of these advances includes the use of psychopharmacological approaches in conjunction with neuroimaging. The paper will introduce the combination of neuroimaging and psychopharmacology as a tool to study neurochemical modulation of human brain function. A review of imaging studies using cholinergic challenges in the context of explicit and implicit learning and memory paradigms is provided which show that cholinergic neurotransmission modulates task-related activity in sensory and frontal cortical brain areas.     

A long-term follow-up case study of crossed aphasia assessed by single-photon emission tomography (SPECT), language, and neuropsychological testing

A 65-year-old man with well-defined crossed aphasia secondary to right cerebral infarction 10 years previously was studied for current language and cognitive abilities and regional cerebral blood flow (rCBF) during cognitive activation measured by single-photon emission tomography (SPECT). Reversed hemispheric lateralization was demonstrated by qualitative aspects of the patient's constructional deficits, dominant parietal lobe signs, and absence of the neglect syndrome. Language activation procedures during SPECT produced focal increases in rCBF to both frontal lobes with a phoneme detection task and to right temporal and parietal lobes with a math task. The authors stress the complexities of assessing brain/language mechanisms in vivo and demonstrate variabilities in rCBF during language activation dependent on task selection.     

Neural circuits underlying the pathophysiology of mood disorders

Although mood disorders constitute leading causes of disability, until recently little was known about their pathogenesis. The delineation of anatomical networks that support emotional behavior (mainly derived from animal studies) and the development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood disorders have enabled significant advances towards elucidating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). In this review, we integrate insights from human and animal studies, which collectively suggest that MDD and BD involve dysfunction within an extended network including the medial prefrontal cortex and anatomically-related limbic, striatal, thalamic and basal forebrain structures.     

Psychotherapy and neuroscience: Towards closer integration

The original aim of psychology was to study and understand the spirit—from the Latin spiritus, literally “breath.” The limitations of scientific methods in the past favoured psychology's aloofness in terms of studying the “intangible,” while medicine developed methods of examining the body (Latin corpus: essential part). Until 20 years ago, knowledge of the localization of brain functions was limited to inferences from clinical observation of brain‐lesioned patients or parallel studies of primate brains. Current neuroscience, with its integrative approach, is bringing together research from molecular through cognitive levels, and psychotherapy has benefited from these findings. Functional neuroimaging studies may make specific and more far‐reaching contributions in this respect, since cerebral dynamics may be observed in vivo and in controlled situations. Methods such as single photon emission tomography, positron emission tomography, and functional magnetic resonance imaging have been able to evaluate the neural correlates involved in psychotherapy for individuals with obsessive‐compulsive disorder, major depression, social phobia, specific phobia, and post‐traumatic disorder. Researchers have found that psychotherapy has the potential to modify dysfunctional neural circuits associated with these disorders. However, precautions are required in constructing feasible designs for neurofunctional investigations. This article reviews the 21 studies that have been published on the subject, and sets out the main advantages and limitations of the technologies used most frequently in protocols involving psychotherapies, and prerequisites for experimental designs. We also pose ways in which the findings from neuroimaging may produce knowledge to guide psychotherapeutic interventions by specifying what should be stimulated in these individuals in order to normalize deficient neural activities.     

Disruption of noradrenergic, but not serotonergic or opiate, functioning blocks both cardiac and behavioral components of the orienting response in preweanling rats

Previous work in this laboratory established that selective attention, as measured by the behavioral and autonomic expressions of the orienting response (OR), is not disrupted by either dopaminergic or cholinergic receptor blockade. The present experiments extended this pharmacological analysis of the OR. In Experiment 1, preweanling rats were injected with methysergide maleate, a serotonin receptor blocker. Neither the behavioral nor the heart rate (HR) component of the OR was attenuated. In Experiment 2, the opiate receptor blocker naltrexone also failed to inhibit the HR and behavioral expressions of the OR. alpha-1 adrenergic receptor blockade with WB-4101 in Experiment 3 abolished both the HR and behavioral ORs to the pulsating tone. In Experiment 4, clonidine, which inhibits release of norepinephrine by stimulating alpha-2 autoreceptors, attenuated both behavioral and HR ORs to the pulsating tone in a dose-dependent manner. These data, in combination with the prior findings, suggest that norepinephrine is critically involved in the central process underlying the OR in the rat. Dopaminergic, cholinergic, serotonergic, and opiate receptor blockades do not impair selective attention as indexed by HR and behavioral ORs to an auditory stimulus. In contrast, disruption of noradrenergic functioning via either alpha-1 receptor blockade or alpha-2 receptor stimulation disrupts both the HR and behavioral components of the OR. These results indicate that integrity of central noradrenergic functioning is essential for expression of the OR and for stimulus-directed attention.